Wilke M. Post  Joanna Widomska  Hilde Grens  Marieke J. H. Coenen  Frank M. J. Martens  Dick A. W. Janssen  Joanna IntHout  Geert Poelmans  Egbert Oosterwijk  Kirsten B. Kluivers 《International journal of molecular sciences》2022,23(6)

Stress urinary incontinence (SUI) is a common and burdensome condition. Because of the large knowledge gap around the molecular processes involved in its pathophysiology, the aim of this review was to provide a systematic overview of genetic variants, gene and protein expression changes related to SUI in human and animal studies. On 5 January 2021, a systematic search was performed in Pubmed, Embase, Web of Science, and the Cochrane library. The screening process and quality assessment were performed in duplicate, using predefined inclusion criteria and different quality assessment tools for human and animal studies respectively. The extracted data were grouped in themes per outcome measure, according to their functions in cellular processes, and synthesized in a narrative review. Finally, 107 studies were included, of which 35 used animal models (rats and mice). Resulting from the most examined processes, the evidence suggests that SUI is associated with altered extracellular matrix metabolism, estrogen receptors, oxidative stress, apoptosis, inflammation, neurodegenerative processes, and muscle cell differentiation and contractility. Due to heterogeneity in the studies (e.g., in examined tissues), the precise contribution of the associated genes and proteins in relation to SUI pathophysiology remained unclear. Future research should focus on possible contributors to these alterations.  相似文献   

    

Gabriella Horvath  Dora Reglodi  Eszter Fabian  Balazs Opper 《International journal of molecular sciences》2022,23(9)

Pituitary adenylate cyclase activating polypeptide (PACAP) was first isolated as a hypothalamic peptide based on its efficacy to increase adenylate cyclase (AC) activity. It has a widespread distribution throughout the body including the nervous system and peripheral organs, where PACAP exerts protective effects both in vivo and in vitro through its anti-apoptotic, anti-inflammatory, and antioxidant functions. The aim of the present paper was to review the currently available literature regarding the effects of PACAP on cell death in vitro in neural and non-neural cells. Among others, its effect on apoptosis can be detected in cerebellar granule cells against different toxic stimuli. Different neural cell types from the cerebral cortex are also prevented from cell death. PACAP also shows effects on cell death in cells belonging to the peripheral nervous system and protects both neural and non-neural cells of sensory organs. In addition, cell survival-promoting effect can be observed in different peripheral organ systems including cardiovascular, immune, respiratory, gastrointestinal, urinary, and reproductive systems. The studies summarized here indicate its noteworthy effect on cell death in different in vitro models, suggesting PACAP’s potential therapeutic usage in several pathological conditions.  相似文献   

    

Linda Schäker-Hübner  Reza Haschemi  Dr. Thomas Büch  Fabian B. Kraft  Birke Brumme  Andrea Schöler  Dr. Robert Jenke  Prof. Dr. Jens Meiler  Prof. Dr. Achim Aigner  Prof. Dr. Gerd Bendas  Prof. Dr. Finn K. Hansen 《ChemMedChem》2022,17(9):e202100755

Herein we report the structure-activity and structure-physicochemical property relationships of a series of class I selective ortho-aminoanilides targeting the “foot-pocket” in HDAC1&2. To balance the structural benefits and the physicochemical disadvantages of these substances, we started with a set of HDACi related to tacedinaline (CI-994) and evaluated their solubility, lipophilicity (log D_7.4) and inhibition of selected HDAC isoforms. Subsequently, we selected the most promising “capless” HDACi and transferred its ZBG to our previously published scaffold featuring a peptoid-based cap group. The resulting hit compound 10 c ( LSH-A54) showed favorable physicochemical properties and is a potent, selective HDAC1/2 inhibitor. The following evaluation of its slow binding properties revealed that LSH-A54 binds tightly to HDAC1 in an induced-fit mechanism. The potent HDAC1/2 inhibitory properties were reflected by attenuated cell migration in a modified wound healing assay and reduced cell viability in a clonogenic survival assay in selected breast cancer cell lines.  相似文献   

    

Robert Gnügge  Thomas Liphardt  Fabian Rudolf 《Yeast (Chichester, England)》2016,33(3):83-98

Shuttle vectors allow for an efficient transfer of recombinant DNA into yeast cells and are widely used in fundamental research and biotechnology. While available shuttle vectors are applicable in many experimental settings, their use in quantitative biology is hampered by insufficient copy number control. Moreover, they often have practical constraints, such as limited modularity and few unique restriction sites. We constructed the pRG shuttle vector series, consisting of single‐ and multi‐copy integrative, centromeric and episomal plasmids with marker genes for the selection in all commonly used auxotrophic yeast strains. The vectors feature a modular design and a large number of unique restriction sites, enabling an efficient exchange of every vector part and expansion of the series. Integration into the host genome is achieved using a double‐crossover recombination mechanism, resulting in stable single‐ and multi‐copy modifications. As centromeric and episomal plasmids give rise to a heterogeneous cell population, an analysis of their copy number distribution and loss behaviour was performed. Overall, the shuttle vector series supports the efficient cloning of genes and their maintenance in yeast cells with improved copy number control. Copyright © 2015 John Wiley & Sons, Ltd.  相似文献   

    

Fabian J. Klüpfel  Holger von Wenckstern  Marius Grundmann 《Advanced Electronic Materials》2016,2(7)

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Fabian Beck  Michael Burch  Stephan Diehl  Daniel Weiskopf 《Computer Graphics Forum》2017,36(1):133-159

Dynamic graph visualization focuses on the challenge of representing the evolution of relationships between entities in readable, scalable and effective diagrams. This work surveys the growing number of approaches in this discipline. We derive a hierarchical taxonomy of techniques by systematically categorizing and tagging publications. While static graph visualizations are often divided into node‐link and matrix representations, we identify the representation of time as the major distinguishing feature for dynamic graph visualizations: either graphs are represented as animated diagrams or as static charts based on a timeline. Evaluations of animated approaches focus on dynamic stability for preserving the viewer's mental map or, in general, compare animated diagrams to timeline‐based ones. A bibliographic analysis provides insights into the organization and development of the field and its community. Finally, we identify and discuss challenges for future research. We also provide feedback from experts, collected with a questionnaire, which gives a broad perspective of these challenges and the current state of the field.  相似文献   

    

Seung‐Heon Lee  Bong Joo Kang  Ba‐Wool Yoo  Seung‐Chul Lee  Seung‐Jun Lee  Mojca Jazbinsek  Hoseop Yun  Fabian Rotermund  O‐Pil Kwon 《Advanced functional materials》2017,27(14)

For terahertz (THz) wave generators based on organic electrooptic crystals, their intrinsic phonon modes are playing an essential role in THz generation characteristics. Here, this study proposes an effective design strategy for THz phonon mode engineering of organic electrooptic salt crystals for efficient optical‐to‐THz frequency conversion. To reduce phonon‐mode intensity, strongly electronegative trifluoromethyl group acting as strong hydrogen‐bond acceptor is incorporated into molecular anions. New 2‐(4‐hydroxy‐3‐methoxystyryl)‐1‐methylquinolinium 4‐(trifluoromethyl)benzenesulfonate (HMQ‐4TFS) crystals exhibit a relatively small absorption coefficient in the THz spectral range between 0.5 and 4 THz, which is attributed to suppressed molecular vibrations due to strong hydrogen bonds involving the 4TFS anion. In addition, HMQ‐4TFS crystals possess a very large macroscopic optical nonlinearity, comparable (or even higher) to benchmark stilbazolium crystals. Based on the low‐intensity THz phonon modes and the large optical nonlinearity, a 0.37 mm thick HMQ‐4TFS crystal pumped with 150 fs infrared laser pulses facilitates very efficient THz wave generation by optical rectification, delivering 23 times higher peak‐to‐peak THz electric field than the widely used standard inorganic ZnTe crystal (1.0 mm thick) and a broader spectral bandwidth. Therefore, strongly electronegative groups introduced into molecular salt electrooptic crystals provide a very promising design strategy of THz phonon mode engineering for developing intense broadband THz sources.  相似文献   

    

Andrea Katharina Lindner  Gert Schachtner  Gennadi Tulchiner  Martin Thurnher  Gerold Untergasser  Peter Obrist  Iris Pipp  Fabian Steinkohl  Wolfgang Horninger  Zoran Culig  Renate Pichler 《International journal of molecular sciences》2021,22(2)

Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1, MSH2, MSH6, and PMS2, and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in MSH2 mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years.  相似文献   

    

Magdalena Wujak  Christine Veith  Cheng-Yu Wu  Tessa Wilke  Zeki Ilker Kanbagli  Tatyana Novoyatleva  Andreas Guenther  Werner Seeger  Friedrich Grimminger  Natascha Sommer  Ralph Theo Schermuly  Norbert Weissmann 《International journal of molecular sciences》2021,22(19)

Increased proliferation of pulmonary arterial smooth muscle cells (PASMCs) in response to chronic hypoxia contributes to pulmonary vascular remodeling in pulmonary hypertension (PH). PH shares numerous similarities with cancer, including a metabolic shift towards glycolysis. In lung cancer, adenylate kinase 4 (AK4) promotes metabolic reprogramming and metastasis. Against this background, we show that AK4 regulates cell proliferation and energy metabolism of primary human PASMCs. We demonstrate that chronic hypoxia upregulates AK4 in PASMCs in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. RNA interference of AK4 decreases the viability and proliferation of PASMCs under both normoxia and chronic hypoxia. AK4 silencing in PASMCs augments mitochondrial respiration and reduces glycolytic metabolism. The observed effects are associated with reduced levels of phosphorylated protein kinase B (Akt) as well as HIF-1α, indicating the existence of an AK4-HIF-1α feedforward loop in hypoxic PASMCs. Finally, we show that AK4 levels are elevated in pulmonary vessels from patients with idiopathic pulmonary arterial hypertension (IPAH), and AK4 silencing decreases glycolytic metabolism of IPAH-PASMCs. We conclude that AK4 is a new metabolic regulator in PASMCs interacting with HIF-1α and Akt signaling pathways to drive the pro-proliferative and glycolytic phenotype of PH.  相似文献   

    

Benjamin C. Krause  Fabian L. Kriegel  Victoria Tartz  Harald Jungnickel  Philipp Reichardt  Ajay Vikram Singh  Peter Laux  Mohamed Shemis  Andreas Luch 《International journal of molecular sciences》2021,22(13)

The interactions between pharmaceuticals and nanomaterials and its potentially resulting toxicological effects in living systems are only insufficiently investigated. In this study, two model compounds, acetaminophen, a pharmaceutical, and cerium dioxide, a manufactured nanomaterial, were investigated in combination and individually. Upon inhalation, cerium dioxide nanomaterials were shown to systemically translocate into other organs, such as the liver. Therefore we picked the human liver cell line HuH-7 cells as an in vitro system to investigate liver toxicity. Possible synergistic or antagonistic metabolic changes after co-exposure scenarios were investigated. Toxicological data of the water soluble tetrazolium (WST-1) assay for cell proliferation and genotoxicity assessment using the Comet assay were combined with an untargeted as well as a targeted lipidomics approach. We found an attenuated cytotoxicity and an altered metabolic profile in co-exposure experiments with cerium dioxide, indicating an interaction of both compounds at these endpoints. Single exposure against cerium dioxide showed a genotoxic effect in the Comet assay. Conversely, acetaminophen exhibited no genotoxic effect. Comet assay data do not indicate an enhancement of genotoxicity after co-exposure. The results obtained in this study highlight the advantage of investigating co-exposure scenarios, especially for bioactive substances.  相似文献